American Indians (or Native Americans) were the indigenous Human inhabitants of the North and South American continents of Earth. Those areas were heavily colonized by more technologically advanced Humans from other continents after the 15th century, leading to the destruction of many indigenous cultures.

In the distant past, extraterrestrials known as Sky Spirits came from the Delta Quadrant to Earth, where they genetically altered a group of primitive Humans. These inheritors carried a similar affinity to the land as the Sky Spirits and spread across the globe, giving rise to the Native American and Amazonian peoples. The Sky Spirits returned but eventually found no trace of their inheritors. Descendants of their inheritors who still had the Sky People appearance, the Rubber Tree People, were however still living in hiding on Earth in the Central Americanrain forest even in the 24th century. (VOY: "Tattoo")

Kukulkan, a benevolent alien being, visited the Mayans and influenced their architecture and agricultural development. Kukulkan was worshiped as a god by the Mayans who encountered him. Kukulkan gave them their remarkably accurate calendar and told them to buitld a city according to its cycles. On the date the city was finished, Kukulkan was supposed to return. The Mayas built their city, but Kukulkan never appeared, as they had only built parts of the design, they never finished the energy amplification system that was supposed to signal Kukulkan. Kulkukan was remembered in many Native American cultures, including the Aztec, Comanche and Toltec peoples. (TAS: "How Sharper Than a Serpent's Tooth")

The Kukulkan visit was not given a specific date but the accounts would seem to suggest an era around 5,000 BC to 2,000 BC.

One group of Native Americans left Earth in the mid-22nd century, dissatisfied with changing Terran attitudes towards nature. After two centuries of searching, they created a new colony on Dorvan V, although the system it was in was disputed ground. With the Federation-Cardassian Treaty, the planet was ceded to the Cardassians, and the USS Enterprise-D was sent to relocate the tribe. The tribe however, decided to stay and leave the Federation. (TNG: "Journey's End")